The objective of this study was to determine the prevalence of lupus-related autoimmunity in a community-based cohort of over 3000 subjects, using a rheumatology registry as a comparison group. Measurements of ANA, anti-dsDNA and a panel of 8 other lupus-related autoantibodies were carried out in 176 subjects from the registry, including patients with SLE or with incomplete lupus (ILE) as well as in first degree relatives (FDRs) of these patients. Similar measurements were then carried out in 3470 samples from an unselected, urban community-based sample that included significant numbers of African-Americans and Hispanics. Correlations with demographic features including gender, race and ethnicity were determined for both groups. Autoantibody profiles in the community-based sample were further evaluated by comparison with diagnostic groups in the registry subjects. ILE patients were found to have autoantibody profiles similar to those seen in SLE patients with the exception of antibodies to dsDNA and chromatin. Some unaffected first degree relatives had multiple autoantibody specificities despite a lack of clinical symptoms. The population-based sample showed a 27% prevalence of ANA positivity, and high ANA levels, defined as greater than 2 standard deviations above the mean, were present in 2.5% of subjects. At least one additional potentially pathogenic autoantibody was present in 1.7%. The prevalence of autoreactivity observed in this population is strikingly similar to previous reports from geographically and ethnically diverse sources, suggesting that underlying genetic and environmental factors driving autoreactivity are widely shared in the human population. Identification of additional markers correlating with development of disease will be needed to determine objective and predictive measures of risk.